Process of making 4-(p-aminobenzenesulphonyl) amino-pyrimidines



PROCESS OF MAKING 4-(p-AMINOBENZENE- SULPHONYL) AMINO-PYRHVIIDINES Werner Loop, Hamburg-Lockstedt, Germany No Drawing. Application May 22, 1953,

Serial No. 356,897 1 Claims priority, application Germany June 15, 1949 2 Claims. (Cl. 260-239.75)

This application is a continuation-in-part-application of my copending application Serial No. 167,486, filed June 10, 1950, for a process of making bis-(benzenesulphonyl)- 4-aminopyrirnidines and now abandoned.

The invention of the present application relates to a process of manufacturing 4-(p-aminobenzenesulphonyl)- aminopyrimidines. One of its objects is to provide an improved method by which a higher yield of the desired products is obtainable than has been possible with the methods hitherto known. Another object is to prepare the products in question with a high degree of purity.

It has now been discovered that 4-(p-aminobenzenesulphonyl)-aminopyrimidines are obtainable in a very good yield and with a high degree of purity by reacting one mol of a dry 4-aminopyrimidine with about two mols of a dry p-acylamino-benzenesulphonic acid halide in the presence of an organic solvent free from hydroxyl groups and of about two mols of an acid binding agent consisting up to 100% of at least one dimethyl-monoalkyl-amin the alkyl group of which contains 1-4 carbon atoms the remaining part of the acid binding agent consisting of at least one other tertiary amine having at least the same capacity of binding hydrogen halides as the said dimethyl-monoalkyl-amin, and subjecting the reaction product thus obtained to a hydrolysis.

A preferred method of my invention comprises a process for the manufacture of 4-(p-aminobenzenesulphonyl)- 2.6-dimethyl-aminopyrimidine which comprises reacting one mol of dry 4-amino-2.6-dimethyl-pyrimidine with about two mols of a dry p-acylamino-benzenesulphonic acid chloride in the presence of an organic solvent free from hydroxyl groups and of about two mols of an acid binding agent consisting up to 100% of at least one dimethyl-monoalkyl-amin the alkyl group of which contains 1-4 carbon atoms the remaining part of the acid binding agent consisting of a trialkylamine whose alkyl groups do not contain more than 4 carbon atoms each at least two alkyl groups however containing more than one carbon atom, and subjecting the reaction product thus obtained to a hydrolysis.

While acetylaminobenzenesulphochloride and carbethoxyarninobenzenesulphochloride are the most preferred acylaminobenzenesulphochlorides used in the process according to the present invention, other acyl-compounds may also be used although less advantageously. Such 7 other acylcompounds are, for instance, the propionyl,

butyryl, valeryl and other lower aliphatic acid compounds 7 or the benzoyl and other aromatic acid compounds.

nited States Patent O ice 2 good yields when used jointly with for instance trimethylamine as is shown by my invention.

The expression about two mols is intended to include the use of more than two mols the use of such an excess being without any disadvantage but otherwise unnecessary.

By my invention it is proved that the reaction between sulphochlorides and 4-aminopyrimidines is greatly influenced by the quality and the quantity of the acid binding agents used, that such commonly used acid binding agents as pyridine and triethylamine are practically useless in this specific reaction and that almost theoreticalyields of an intermediate product that can be hydrolyzed without intermediate purification are obtainable when p'ro- To 52.0 grams of dry acetylsulphanilic acid chloride are added 12.3 grams of 4-amino-2.G-dimethylpyrimidine I thoroughly mixed whereby care is being taken that the aqueous solution at all times reacts neutral when tested against litmus. After cooling, the solution is filtered and the filter residues washed with plenty of water. yield amounts to l00%. The product thus obtained is hydrolysed with caustic soda lye whereby the 4-(p-aminobenzenesulphonyl)-amino-2.6-dimethylpyrirnidine is' obtained in a high yield and purity.

l Example 2 16.5 grams of 4-amino-2.6-diethyl-S-methylpyrimidine and 200 ccm. of methylene chloride are added to 52.0 grams of water-free acetylsulphanilic acid While agitating and cooling, but excluding water, 65 ccm. of a water-free benzene trimethylamine solution, containing 13.0 grams of trimethylarnine, are introduced into the mixture. After introduction of the trimethylamine, agitating is continued for a few hours whereupon the organic solvents are evaporated. The residues are then diluted with 300 ccm. water and the aqueous solution is agitated for 30 minutes while at the same time its temperature is raised to 50-60 C., care being taken that the solution at all times reacts neutral. The yield amounts to at least 90% of the theoretical yield. The product thus obtained can be hydrolysed as shown in Example 1 without any intermediate purification.

Example 3 grams of dry acetylsulphanilic acid chloride, and 200 ccm.

methylenchloride are mixed with- 65 ccm. of a benzene solution of water-free trimethylarnine', containing 13.0 grams trimethylamine, while excluding water and agitatiug and cooling. The further procedure is similar to the one described in Examples 1 and 2.

Example 4 12.3 grams (0.1 mol) finely powdered 4-an1ino-2,6-dimethylpyrimidine and 46.8 grams (0.2 mol) dry p-acetylsulphanilic-acid chloride are mixed while stirring with 200 ccm. methylene chloride. To this mixture there are added while agitating, weakly cooling and excluding water rammed Dec. 4, 1956 chloride. 7

3.0 (0.05 mol) trimethylamine dissolved in 15 ccm. ben

After, theaddition. oi the tertiary. amines. agitation. is continued for six hours whereupon the: organiesolvents.

are. evaporated asfar as; possible; The distillationresidues are heated with 300 ccm. water. until the organic solvents are. completely. driven. oft. The. aqueous.- reaction mixture. including the solid, almost colourless. precipitate is kept for- 12 hoursim an iceboxand then filtered. The filten residue is thoroughly washed with water. and then exhaustively. extracted with a 5%. sodalye. The residue thus. obtained. consists of bis:(pacetaminobenzenesulphonyl)=4 arnino-2.6-dimethylpyrimidine. By neutralising; thez mother. lye. there. are obtained further quantities of. mono- (1p-acetaminobenzenesulphonyl) 4-amino-2 .6-dimethylpyrimidine.

By uniting the. saidintermediate products and boiling with 6 times. the. volume of, soda-lye and. then.neu tralising the reaction. mixture there is. obtained the: 4-(paminobenzenesulphonylz) amino-2.6 dirnethylpynimidine having a melting point of 239 C.

Example 5 12.3 grams(0.1 mol). finely. powdered 4-amino-2.6-dimethylpyrimidine and 46.8 grams:(0.2. mol) dry p-acetylsulphanilic-acid-chloride are mixed while stirring with 100 ccm. methylene chloride. To this mixture are added 7 while agitating and excluding water 3.0 grams (0.05 mol) trimethylamine dissolved in ccm. benzene and then 13.4 grams (approximately 0.15 mol) dry diethyl-monomethyl-amine dissolved in 15 com. benzene. After agitating for 6 hours at room temperature the reaction mixture is worked up as described irr-Example 1. Hydrolysed according to the method of Example 1, there is obtained the 4'-(p-aminobenzenesul'phonyl) amino 2.4- dimethylpyrimidine in' a high yield and witha pure quality.

I claim:

1. A method of manufacturing 4-(p-aminobenzene- 'sulphonyD-aminopyrimidines; comprising the steps of re acting one mol of a dry 4-amino-pyrimidine with about two mols of a. dry p-acylarninobenzenesulphonic acid halide in the presence of an organic solvent free of hydroxyl groups and inthe further presence of about two mols of trimethylamine, thereby forming a reaction product; and subjecting said reaction product to hydrolysis.

2. A method" of manufacturing 4-(p-aminobenzenesulfonyl)'-amino'-2,6 dimethylpyrimidine, comprising the steps of reacting one mol of dry- 4"-arnino- 2,6-dimethylpyrimidine with about two-mol's of dry p-acetylsulphanilic acid chloride in thepresenceofan organic solvent free of hydroxyl groups-and in the further presence of about two mols of trimethylamine, thereby forming a reaction prod net; and subjecting said reaction product to hydrolysis.

References Citedrin. the file of this patent UNITED STATES PATENTS 2,429,184- Hartmann-etal. Oct. 14, 1947 2,430,439 Winnek et al Nov. 4, 1947 2,508,450 Demolis May 23, 1950 FOREIGN PATENTS 495,650 Belgium May 31, 1950 547,976 Great Britain Sept. 21, 1942 582,149 Great Britain Nov. 6, 1946 886,009 France June 15, 1943 990,388 France June 6, 1951 OTHER REFERENCES- Ser. No. 334,990, Foldi et al. (A. P. C.), published Apr. 20, 1943. 

2. A METHOD OF MANUFACTURING 4-(P-AMINOBENZENESULFONYL)-AMINO-2,6-DIMETHYLPYRIMIDINE, COMPRISING THE STEPS OF REACTING ONE MOL OF DRY 4-AMINO-2,6-DIMETHYLPYRIMIDINE WITH ABOUT TWO MOLS OF DRY P-ACETYLSULPHANILIC ACID CHLORIDE IN THE PRESENCE OF AN ORGANIC SOLVENT FREE OF HYDROXYL GROUPS AND IN THE FURTHER PRESENCE OF ABOUT TWO MOLS OF TRIMETHYLAMINE, THEREBY FORMING A REACTION PRODUCT; AND SUBJECTING SAID REACTION PRODUCT TO HYDROLYSIS. 